Project Summary Coccidioidomycosis (Valley Fever) is a serious public health problem for the Southwestern United States and all who visit there. A small proportion of infections result in progressive, debilitating, even life-threatening illness (disseminated coccidioidomycosis or DCM). All evidence suggests that this heightened susceptibility is due to differences in immunologic responses of the patient, clearly understood in overtly immunodeficient persons (i.e., those with AIDS) but not understood for the large majority of otherwise healthy patients with DCM. The NIAID intramural PI (Dr. Steven Holland) has identified inheritable gene mutations in a few patients each of which are associated with DCM. He has also found additional patients with DCM to have rare gene variants possibly producing deleterious consequences. These discoveries provide clues to the pathways that might be deregulated in other patients with DCM but who do not have such readily identifiable genetic alternations. This project builds on the ongoing collaboration between Dr. Holland and Dr. John Galgiani, University of Arizona (UA) Director of the Valley Fever Center for Excellence, to maintain a referral path for subjects living in Arizona to the existing program at the NIH Clinical Center. This work will better define the functional consequences of the Mendelian mutations that Dr. Holland has identified and how those differences permit DCM to occur. A second aim is to analyze gene expression of peripheral blood mononuclear cells of patients with DCM not associated with Mendelian mutations in comparison to persons who control coccidioidal infection without becoming ill. Such comparisons may identify dysregulated patterns of response and suggest which putatively deleterious variants in such patients might be responsible. A third aim is to genetically introduce Mendelian mutations associated with human DCM (such as one found by Dr. Holland in STAT4) into a mouse strain normally resistant to coccidioidal dissemination to determine if such mutations result in increased DCM. If so, we can also discover whether it is possible to prevent DCM in the transfected mice by immunization. The murine studies will use containment facilities available at the UA and not currently available at the NIH. As a result of this work, it may be possible to identify persons who, if infected, will develop DCM. Also, our findings may suggest new approaches to therapy or preventative vaccines.